Safety and effects of a therapeutic 15 Hz rTMS protocol administered at different suprathreshold intensities in able-bodied individuals.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) remains a promising strategy for neurorehabilitation. The stimulation intensity (SI) influences the aftereffects observed. Here, we examined whether single sessions of a 15 Hz rTMS protocol, administered at suprathreshold SI, can be safely administered to able-bodied (AB) individuals. Six right-handed men were included in this pilot study. HF-rTMS was delivered over the right M1, in 10 trains of 75 biphasic stimuli at 15 Hz, at 105-120% of the individual resting motor threshold (RMT). To assess safety, electromyography (EMG) was monitored to control for signs of spread of excitation and brief EMG burst (BEB) after stimulation. Additionally, TMS side effects questionnaires and the numeric rating scale (NRS) were administered during each session. We assessed corticospinal excitability (CSE) and motor performance changes with measures of resting (rMEP) and active (aMEP) motor evoked potential and grip strength and box and blocks test (BBT) scores, respectively. Overall, the sessions were tolerated and feasible without any pain development. However, EMG analysis during 15 Hz rTMS administration revealed increased BEB frequency with SI. Statistical models revealed an increase of CSE at rest (rMEP) but not during active muscle contraction (aMEP). No linear relationship was observed between 15 Hz rTMS SI and rMEP increase. No significant changes were highlighted for motor performance measures. Although feasible and tolerable by the AB individuals tested, the results demonstrate that when administered at suprathreshold intensities (≥ 105% RMT) the 15 Hz rTMS protocol reveals signs of persistent excitation, suggesting that safety precautions and close monitoring of participants should be performed when testing such combinations of high-intensity and high-frequency stimulation protocols. The results also give insight into the nonlinear existent relationship between the SI and HF-rTMS effects on CSE.NEW & NOTEWORTHY The results of this pilot study show the effects of a therapeutically promising 15 Hz repetitive transcranial magnetic stimulation (rTMS) protocol, administered at different suprathreshold intensities in able-bodied individuals. Although tolerable and feasible with a neuromodulatory potential, 15 Hz rTMS might result in persistent excitability that needs to be closely monitored if administered at suprathreshold stimulation intensity. These results reaffirm the importance of feasibility studies, especially in translational animal-to-human research.

Aging-induced alterations in EEG spectral power associated with graded force motor tasks.

BACKGROUND: It has been demonstrated that in young and healthy individuals, there is a strong association between the amplitude of EEG-derived motor activity-related cortical potential or EEG spectral power (ESP) and voluntary muscle force. This association suggests that the motor-related ESP may serve as an index of central nervous system function in controlling voluntary muscle activation Therefore, it may potentially be used as an objective marker to track changes in functional neuroplasticity due to neurological disorders, aging, and following rehabilitation therapies. To this end, the relationship between the band-specific ESP-combined spectral power of EEG oscillatory and aperiodic (noise) components-and voluntary elbow flexion (EF) force has been analyzed in elder and young individuals. METHODS: 20 young (22.6 ± 0.87 year) and 28 elderly (74.79 ± 1.37 year) participants performed EF contractions at 20%, 50%, and 80% of maximum voluntary contraction (MVC) while high-density EEG signals were recorded. Both the absolute and relative ESPs were computed for the EEG frequency bands of interest. RESULTS: The MVC force generated by the elderly was foreseeably lower than that of the young participants. Compared to young, the elderly cohort's (1) total ESP was significantly lower for the high (80% MVC) force task; (2) relative ESP in beta band was significantly elevated for the low and moderate (20% MVC and 50% MVC) force tasks; (3) absolute ESP failed to have a positive trend with force for EEG frequency bands of interest; and (4) beta-band relative ESP did not exhibit a significant decrease with increasing force levels. CONCLUSIONS: As opposed to young subjects, the beta-band relative ESP in elderly did not significantly decrease with increasing EF force values. This observation suggests the use of beta-band relative ESP as a potential biomarker for age-related motor control degeneration.

Targeted Selection of Stimulation Parameters for Restoration of Motor and Autonomic Function in Individuals With Spinal Cord Injury.

STUDY DESIGN: This is a report of methods and tools for selection of task and individual configurations targeted for voluntary movement, standing, stepping, blood pressure stabilization, and facilitation of bladder storage and emptying using tonic-interleaved excitation of the lumbosacral spinal cord. OBJECTIVES: This study aimed to present strategies used for selection of stimulation parameters for various motor and autonomic functions. CONCLUSIONS: Tonic-interleaved functionally focused neuromodulation targets a myriad of consequences from spinal cord injury with surgical implantation of the epidural electrode at a single location. This approach indicates the sophistication of the human spinal cord circuitry and its important role in the regulation of motor and autonomic functions in humans.

Australian statewide virtual care competency-based education framework for the healthcare workforce: a Delphi study.

This study aimed to establish shared interprofessional competencies across health professions that promote education, communication, and teamwork, preparing the virtual care workforce to work collaboratively with the patient and their carers, family members, and communities to improve health outcomes. A modified, two-round Delphi process was undertaken with an interprofessional panel selected from the public health sector workforce across one Australian state. Sixty-nine panelists participated in Round 1 and 40 panelists participated in Round 2. Fifty-eight competencies across seven domains were established to support an interprofessional approach to virtual care provision: compliance, professional practice, patient safety, communication, interprofessional collaboration, patient assessment and care planning/delivery/coordination. This virtual care education framework may assist different health disciplines to develop, revise or map new or existing undergraduate or postgraduate education programs or design professional development activities. Drawing upon the expertise of a broad range of health professionals in its development, this education framework focuses on improving interprofessional collaboration in virtual care settings.

Generation of a Reference Dataset to Permit the Calculation of T-scores at the Distal Femur and Proximal Tibia in Persons with Spinal Cord Injury.

Persons with traumatic spinal cord injury (SCI) have severe bone loss below the level of lesion with the distal femur (DF) and proximal tibia (PT) being the skeletal regions having the highest risk of fracture. While a reference areal bone mineral density (aBMD) database is available at the total hip (TH) using the combined National Health and Nutrition Examination Survey (NHANES) III study and General Electric (GE) combined (GE/NHANES) to calculate T-score (T-scoreGE/NHANES), no such reference database exists for aBMD of the DF, and PT. The primary objectives of this study were (1) to create a reference dataset of young-healthy able-bodied (YHAB) persons to calculate T-score (T-scoreYHAB) values at the DF and PT, (2) to explore the impact of time since injury (TSI) on relative bone loss in the DF and PT regions using the two computation models to determine T-score values, and (3) to determine agreement between T-score values for a cohort of persons with SCI using the (T-scoreYHAB) and (T-scoreGE/NHANES) reference datasets. A cross-sectional prospective data collection study. A Department of Veterans Affairs Medical Center and a Private Rehabilitation Hospital. A normative reference aBMD database at the DF and PT was collected in 32 male and 32 female Caucasian YHAB participants (n=64) and then applied to calculate T-score values at the DF and PT in 105 SCI participants from a historical cohort. The SCI participants were then grouped based on TSI epochs (E-I: TSI < 1y, E-II: TSI 1-5y, E-III: TSI 6-10y, E-IV: TSI 11-20y, E-V: TSI > 20y). N/A. The knee and hip aBMD values were obtained by dual energy X-ray absorptiometry (GE Lunar iDXA) using standard clinical software for proximal femur orthopedic knee software applications. There were no significant differences in mean aBMD values across the four YHAB age subgroups (21-25, 26-30, 31-35, and 36-40 yr of age) at the TH, DF, and PT; mean aBMD values were higher in men compared to the women at all skeletal regions of interest. Using the mean YHAB aBMD values to calculate T-score values at each TSI epoch for persons with SCI, T-score values decreased as a function of TSI, and they continued to decline for 11-20 yr. Moderate kappa agreement was noted between the YHAB and the GE/NHANES reference datasets for the T-score cutoff criteria accepted to diagnose osteoporosis (i.e., SD <-2.5). A homogeneous reference dataset of YHAB aBMD values at the DF and PT was applied to calculate T-score values in persons with chronic SCI. There was a moderate level of agreement at the TH between the YHAB and GE/NHANES reference datasets when applying the conventional T-score cutoff value for the diagnosis of osteoporosis.

Walking improvement in chronic incomplete spinal cord injury with exoskeleton robotic training (WISE): a randomized controlled trial.

STUDY DESIGN: Clinical trial. OBJECTIVE: To demonstrate that a 12-week exoskeleton-based robotic gait training regimen can lead to a clinically meaningful improvement in independent gait speed, in community-dwelling participants with chronic incomplete spinal cord injury (iSCI). SETTING: Outpatient rehabilitation or research institute. METHODS: Multi-site (United States), randomized, controlled trial, comparing exoskeleton gait training (12 weeks, 36 sessions) with standard gait training or no gait training (2:2:1 randomization) in chronic iSCI (>1 year post injury, AIS-C, and D), with residual stepping ability. The primary outcome measure was change in robot-independent gait speed (10-meter walk test, 10MWT) post 12-week intervention. Secondary outcomes included: Timed-Up-and-Go (TUG), 6-min walk test (6MWT), Walking Index for Spinal Cord Injury (WISCI-II) (assistance and devices), and treating therapist NASA-Task Load Index. RESULTS: Twenty-five participants completed the assessments and training as assigned (9 Ekso, 10 Active Control, 6 Passive Control). Mean change in gait speed at the primary endpoint was not statistically significant. The proportion of participants with improvement in clinical ambulation category from home to community speed post-intervention was greatest in the Ekso group (>1/2 Ekso, 1/3 Active Control, 0 Passive Control, p < 0.05). Improvements in secondary outcome measures were not significant. CONCLUSIONS: Twelve weeks of exoskeleton robotic training in chronic SCI participants with independent stepping ability at baseline can improve clinical ambulatory status. Improvements in raw gait speed were not statistically significant at the group level, which may guide future trials for participant inclusion criteria. While generally safe and tolerable, larger gains in ambulation might be associated with higher risk for non-serious adverse events.

Safety and efficacy of transcranial direct current stimulation in upper extremity rehabilitation after tetraplegia: protocol of a multicenter randomized, clinical trial.

STUDY DESIGN: A multisite, randomized, controlled, double-blinded phase I/II clinical trial. OBJECTIVE: The purpose of this clinical trial is to evaluate the safety, feasibility and efficacy of pairing noninvasive transcranial direct current stimulation (tDCS) with rehabilitation to promote paretic upper extremity recovery and functional independence in persons living with chronic cervical spinal cord injury (SCI). SETTING: Four-site trial conducted across Cleveland Clinic, Louis Stokes Veterans Affairs Medical Center of Cleveland and MetroHealth Rehabilitation Rehabilitation Institute of Ohio, and Kessler Foundation of New Jersey. METHODS: Forty-four adults (age ≥18 years) with tetraplegia following cervical SCI that occurred ≥1-year ago will participate. Participants will be randomly assigned to receive anodal tDCS or sham tDCS given in combination with upper extremity rehabilitation for 15 sessions each over 3-5 weeks. Assessments will be made twice at baseline separated by at least a 3-week interval, once at end-of-intervention, and once at 3-month follow-up. PRIMARY OUTCOME MEASURE(S): Primary outcome measure is upper extremity motor impairment assessed using the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) scale. Functional abilities will be assessed using Capabilities of Upper Extremity-Test (CUE-T), while functional independence and participation restrictions will be evaluated using the self-care domain of Spinal Cord Independent Measure (SCIM), and Canadian Occupational Performance Measure (COPM). SECONDARY OUTCOME MEASURES: Treatment-associated change in corticospinal excitability and output will also be studied using transcranial magnetic stimulation (TMS) and safety (reports of adverse events) and feasibility (attrition, adherence etc.) will also be evaluated. TRIAL REGISTRATION: ClincalTrials.gov identifier NCT03892746. This clinical trial is being performed at four sites within the United States: Cleveland Clinic (lead site), Louis Stokes Cleveland Veterans Affairs Medical Center (VAMC) and MetroHealth Rehabilitation Institute in Ohio, and Kessler Foundation in New Jersey. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office.

Clinician Perceptions of Robotic Exoskeletons for Locomotor Training After Spinal Cord Injury: A Qualitative Approach.

OBJECTIVE: To describe the experiences of clinicians who have used robotic exoskeletons in their practice and acquire information that can guide clinical decisions and training strategies related to robotic exoskeletons. DESIGN: Qualitative, online survey study, and 4 single-session focus groups followed by thematic analysis to define themes. SETTING: Focus groups were conducted at 3 regional rehabilitation hospitals and 1 Veteran's Administration (VA) Medical Center. PARTICIPANTS: Clinicians (N=40) reported their demographic characteristics and clinical experience using robotic exoskeletons. Twenty-nine clinicians participated in focus groups at regional hospitals that use robotic exoskeletons, as well as 1 VA Medical Center. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Clinicians' preferences, experiences, training strategies, and clinical decisions on how robotic exoskeleton devices are used with Veterans and civilians with spinal cord injury. RESULTS: Clinicians had an average of 3 years of experience using exoskeletons in clinical and research settings. Major themes emerging from focus group discussions included appropriateness of patient goals, patient selection criteria, realistic patient expectations, patient and caregiver training for use of exoskeletons, perceived benefits, preferences regarding specific exoskeletons, and device limitations and therapy recommendations. CONCLUSIONS: Clinicians identified benefits of exoskeleton use including decreased physical burden and fatigue while maximizing patient mobility, increased safety of clinicians and patients, and expanded device awareness and preferences. Suitability of exoskeletons for patients with various characteristics and managing expectations were concerns. Clinicians identified research opportunities as technology continues to advance toward safer, lighter, and hands-free devices.

Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation.

STUDY DESIGN: This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation. OBJECTIVES: 1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation. MATERIALS AND METHODS: Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury. CONCLUSIONS: Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as "placebo" require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.

Cardiovascular Autonomic Dysfunction in Spinal Cord Injury: Epidemiology, Diagnosis, and Management.

Spinal cord injury (SCI) disrupts autonomic circuits and impairs synchronistic functioning of the autonomic nervous system, leading to inadequate cardiovascular regulation. Individuals with SCI, particularly at or above the sixth thoracic vertebral level (T6), often have impaired regulation of sympathetic vasoconstriction of the peripheral vasculature and the splanchnic circulation, and diminished control of heart rate and cardiac output. In addition, impaired descending sympathetic control results in changes in circulating levels of plasma catecholamines, which can have a profound effect on cardiovascular function. Although individuals with lesions below T6 often have normal resting blood pressures, there is evidence of increases in resting heart rate and inadequate cardiovascular response to autonomic provocations such as the head-up tilt and cold face tests. This manuscript reviews the prevalence of cardiovascular disorders given the level, duration and severity of SCI, the clinical presentation, diagnostic workup, short- and long-term consequences, and empirical evidence supporting management strategies to treat cardiovascular dysfunction following a SCI.

Users with spinal cord injury experience of robotic Locomotor exoskeletons: a qualitative study of the benefits, limitations, and recommendations.

BACKGROUND: Persons with spinal cord injury (SCI) may experience both psychological and physiological benefits from robotic locomotor exoskeleton use, and knowledgeable users may have valuable perspectives to inform future development. The objective of this study is to gain insight into the experiences, perspectives, concerns, and suggestions on the use of robotic locomotor exoskeletons by civilians and veterans living with SCI. METHODS: Participants reported their demographic characteristics and the extent of robotic exoskeleton use in an online survey. Then, 28 experienced robotic locomotor exoskeleton users participated in focus groups held at three regional hospitals that specialize in rehabilitation for persons with SCI. We used a qualitative description approach analysis to analyze the data, and included thematic analysis. RESULTS: Participants expressed that robotic exoskeletons were useful in therapy settings but, in their current form, were not practical for activities of daily living due to device limitations. Participants detailed the psychological benefits of being eye-level with their non-disabled peers and family members, and some reported physiologic improvements in areas such as bowel and bladder function. Participants detailed barriers of increased fatigue, spasticity, and spasms and expressed dissatisfaction with the devices due to an inability to use them independently and safely. Participants provided suggestions to manufacturers for technology improvements. CONCLUSIONS: The varied opinions and insights of robotic locomotor exoskeletons users with SCI add to our knowledge of device benefits and limitations.

Progressive Sublesional Bone Loss Extends into the Second Decade After Spinal Cord Injury.

OBJECTIVE: The rate of areal bone mineral density (aBMD) loss at the knee (distal femur (DF) and proximal tibia ) and hip (femoral neck (FN) and total hip (TH)) was determined in persons with traumatic spinal cord injury (SCI) who were stratified into subgroups based on time since injury (TSI). DESIGN: Cross-sectional retrospective review. SETTING: Department of Veterans Affairs Medical Center and Private Rehabilitation Hospital. PARTICIPANTS: Data on 105 individuals with SCI (TSI ≤12 months, n = 19; TSI 1-5 years, n = 35; 6-10 years, n = 19; TSI 11-20 years, n = 16; TSI >20 years, n = 15) and 17 able-bodied reference (ABref) controls. INTERVENTIONS: NA Main Outcome Measures: The knee and hip aBMD values were obtained by dual energy X-ray absorptiometry (GE Lunar iDXA) using standard clinical software for the proximal femur employed in conjunction with proprietary research orthopedic knee software applications. Young-normal (T-score) and age-matched (Z-scores) standardized scores for the FN and TH were obtained using the combined GE Lunar/National Health and Nutrition Examination Survey (NHANES III) combined reference database. RESULTS: When groups were stratified and compared as epochs of TSI, significantly lower mean aBMD and reference scores were observed as TSI increased, despite similar mean ages of participants among the majority of TSI epoch subgroups. Loss in aBMD occurred at the distal femur (DF), proximal tibia (PT), FN, and TH with 46%, 49%, 32%, and 43% of the variance in loss, respectively, described by the exponential decay curves with a time to steady state (tss) occurring at 14.6, 11.3, 14, and 6.2 years, respectively, after SCI. CONCLUSIONS: Sublesional bone loss after SCI was marked and occurred as an inverse function of TSI. For aBMD at the hip and knee, tss extended into the second decade after SCI.

Longitudinal Recovery and Reduced Costs After 120 Sessions of Locomotor Training for Motor Incomplete Spinal Cord Injury.

OBJECTIVE: To determine the impact of long-term, body weight-supported locomotor training after chronic, incomplete spinal cord injury (SCI), and to estimate the health care costs related to lost recovery potential and preventable secondary complications that may have occurred because of visit limits imposed by insurers. DESIGN: Prospective observational cohort with longitudinal follow-up. SETTING: Eight outpatient rehabilitation centers that participate in the Christopher & Dana Reeve Foundation NeuroRecovery Network (NRN). PARTICIPANTS: Individuals with motor incomplete chronic SCI (American Spinal Injury Association Impairment Scale C or D; N=69; 0.1-45y after SCI) who completed at least 120 NRN physical therapy sessions. INTERVENTIONS: Manually assisted locomotor training (LT) in a body weight-supported treadmill environment, overground standing and stepping activities, and community integration tasks. MAIN OUTCOME MEASURES: International Standards for Neurological Classification of Spinal Cord Injury motor and sensory scores, orthostatic hypotension, bowel/bladder/sexual function, Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI), Berg Balance Scale, Modified Functional Reach, 10-m walk test, and 6-minute walk test. Longitudinal outcome measure collection occurred every 20 treatments and at 6- to 12-month follow-up after discharge from therapy. RESULTS: Significant improvement occurred for upper and lower motor strength, functional activities, psychological arousal, sensation of bowel movement, and SCI-FAI community ambulation. Extended training enabled minimal detectable changes at 60, 80, 100, and 120 sessions. After detectable change occurred, it was sustained through 120 sessions and continued 6 to 12 months after treatment. CONCLUSIONS: Delivering at least 120 sessions of LT improves recovery from incomplete chronic SCI. Because walking reduces rehospitalization, LT delivered beyond the average 20-session insurance limit can reduce rehospitalizations and long-term health costs.

Cyclogram based Joint Symmetry Assessment after Utilization of a Foot Drop Stimulator during Post Stroke Hemiplegic Gait.

In the absence of standardized symmetry assessments, quantifying symmetry based on the kinematic evolution of lower extremity joints can elucidate gait irregularities. The objective was to develop a novel cyclogram based symmetry (CBS) method to quantify lower extremity joints' symmetry and assess the effect of 6-month utilization of foot drop stimulator (FDS) on CBS of the lower limbs during hemiplegic gait post stroke. Twenty-four participants (13 stroke and 11 healthy controls (HC)) performed 10 walking trials at a free cadence on level ground. Symmetry values were computed using geometric properties of bilateral cyclograms obtained from normalized sagittal ankle, knee and hip kinematics. CBS and traditional temporospatial symmetry values were compared between the two groups using independent sample t-test. Effect of FDS utilization on symmetry was assessed by paired sample t- test computed at baseline and 6-month follow up. The CBS method successfully showed that the HC group was significantly more symmetrical at the ankle (p=0.001), knee (p=0.001) and hip (p<0.005) compared with the stroke group. The stroke group showed significant increment in hip symmetry with FDS at baseline but did not show any significant CBS changes at follow up. Pearson correlations revealed that hip and knee CBS had a significant influence on overall walking speed. The CBS method presents a unique approach to calculate symmetry based on the kinematics of lower extremities during gait.

Dose-dependent effects of siRNA-mediated inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey.

SREBP cleavage-activating protein (SCAP) is a key protein in the regulation of lipid metabolism and a potential target for treatment of dyslipidemia. SCAP is required for activation of the transcription factors SREBP-1 and -2. SREBPs regulate the expression of genes involved in fatty acid and cholesterol biosynthesis, and LDL-C clearance through the regulation of LDL receptor (LDLR) and PCSK9 expression. To further test the potential of SCAP as a novel target for treatment of dyslipidemia, we used siRNAs to inhibit hepatic SCAP expression and assess the effect on PCSK9, LDLR, and lipids in mice and rhesus monkeys. In mice, robust liver Scap mRNA knockdown (KD) was achieved, accompanied by dose-dependent reduction in SREBP-regulated gene expression, de novo lipogenesis, and plasma PCSK9 and lipids. In rhesus monkeys, over 90% SCAP mRNA KD was achieved resulting in approximately 75, 50, and 50% reduction of plasma PCSK9, TG, and LDL-C, respectively. Inhibition of SCAP function was demonstrated by reduced expression of SREBP-regulated genes and de novo lipogenesis. In conclusion, siRNA-mediated inhibition of SCAP resulted in a significant reduction in circulating PCSK9 and LDL-C in rodent and primate models supporting SCAP as a novel target for the treatment of dyslipidemia.

Glucagon receptor antagonism induces increased cholesterol absorption.

Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.

Acute hemodynamic and renal effects of glucagon-like peptide 1 analog and dipeptidyl peptidase-4 inhibitor in rats.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors are a newer class of antidiabetics named as incretin-based therapy. In addition to the homeostatic control of glucose, the incretin-based therapy has shown beneficial effects on the cardiovascular system in preclinical and clinical studies. However, there is limited information on their renal effects. To this end, we assessed the acute hemodynamic and renal effects of a GLP-1 analog, Liraglutide, and a DPP4 inhibitor, MK-0626. METHODS: Experiments were performed in anesthetized male Sprague-Dawley rats. Three ascending doses of Liraglutide (3, 9, and 27 nmol/kg/h) or MK-0626 (1 mg/kg) with or without GLP-1 peptide (2.4, 4.8, or 9.6 pmol/kg/min) were administered. Blood pressure (BP) and heart rate (HR) were recorded from an indwelling catheter. Glomerular filtration rate (GFR) and renal blood flow (RBF) were assessed by inulin and para-aminohippurate clearance, respectively. Renal excretory function was assessed in metabolic studies. RESULTS: Both Liraglutide and MK-0626 plus GLP-1 evoked significant diuretic and natriuretic responses and increased GFR. MK-0626 alone increased RBF. Liraglutide at 27 nmol//kg/h and MK-0626 plus GLP-1 at 9.6 pmol/kg/min also increased HR, whereas BP was not affected. CONCLUSION: The results of the present study demonstrated that a GLP-1 analog and a DPP4 inhibitor may have beneficial effects on renal sodium and water handling. Additionally, the DPP4 inhibitor, MK-0626, favorably affects renal hemodynamics by increasing RBF. However, exceedingly high levels of GLP-1 receptor agonists may adversely affect the cardiovascular system in acute setting, as demonstrated by an acute increase in HR.

Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1.

Gene deletion studies in mice have revealed critical roles for IL (interleukin)-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucus secretion. We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit that prevent activation of the receptor complex by both IL-4 and IL-13. We describe the crystal structures of the Fab fragment of antibody 10G5H6 alone and in complex with D3 (ectodomain 3) of IL-13Rα1. Although the structure showed significant domain swapping within a D3 dimer, we showed that Arg(230), Phe(233), Tyr(250), Gln(252) and Leu(293) in each D3 monomer and Ser(32), Asn(102) and Trp(103) in 10G5H6 Fab are the key interacting residues at the interface of the 10G5H6 Fab-D3 complex. One of the most striking contacts is the insertion of the ligand-contacting residue Leu(293) of D3 into a deep pocket on the surface of 10G5H6 Fab, and this appears to be a central determinant of the high binding affinity and neutralizing activity of the antibody.

Spinal cord transcutaneous stimulation in cervical spinal cord injury: A review examining upper extremity neuromotor control, recovery mechanisms, and future directions.

Cervical spinal cord injury (SCI) results in significant sensorimotor impairments below the injury level, notably in the upper extremities (UE), impacting daily activities and quality of life. Regaining UE function remains the top priority for individuals post cervical SCI. Recent advances in understanding adaptive plasticity within the sensorimotor system have led to the development of novel non-invasive neurostimulation strategies, such as spinal cord transcutaneous stimulation (scTS), to facilitate UE motor recovery after SCI. This comprehensive review investigates the neuromotor control of UE, the typical recovery trajectories following SCI, and the therapeutic potential of scTS to enhance UE motor function in individuals with cervical SCI. Although limited in number with smaller sample sizes, the included research articles consistently suggest that scTS, when combined with task-specific training, improves voluntary control of arm and hand function and sensation. Furthermore, the reported improvements translate to recovery of various UE functional tasks and positively impact the quality of life in individuals with cervical SCI. Several methodological limitations, including stimulation site selection and parameters, training strategies and sensitive outcome measures, require further advancements to allow successful translation of scTS from research to clinical settings. This review also summarizes the current literature and proposes future directions to support establishing approaches for scTS as a viable neuro-rehabilitative tool.

Robotic Postural Training With Epidural Stimulation for the Recovery of Upright Postural Control in Individuals With Motor Complete Spinal Cord Injury: A Pilot Study.

Activity-based training and lumbosacral spinal cord epidural stimulation (scES) have the potential to restore standing and walking with self-balance assistance after motor complete spinal cord injury (SCI). However, improvements in upright postural control have not previously been addressed in this population. Here, we implemented a novel robotic postural training with scES, performed with free hands, to restore upright postural control in individuals with chronic, cervical (n = 5) or high-thoracic (n = 1) motor complete SCI, who had previously undergone stand training with scES using a walker or a standing frame for self-balance assistance. Robotic postural training re-enabled and/or largely improved the participants' ability to control steady standing, self-initiated trunk movements and upper limb reaching movements while standing with free hands, receiving only external assistance for pelvic control. These improvements were associated with neuromuscular activation pattern adaptations above and below the lesion. These findings suggest that the human spinal cord below the level of injury can generate meaningful postural responses when its excitability is modulated by scES, and can learn to improve these responses. Upright postural control improvements can enhance functional motor recovery promoted by scES after severe SCI.